This is an application for competitive renewal of RO1 DK31369. Irritable bowel syndrome affects 10% of U.S. adults and costs $1.9 billion annually. However, 75% of excess health care visits and 66% of excess costs are for non-gastrointestinal, comorbid conditions. The aim of the proposed studies is to determine whether irritable bowel is uniquely associated with specific comorbid conditions, which would suggest shared pathophysiology, or whether comorbidity is an expression of psychological contributions to the etiology of irritable bowel. Specific hypotheses are (1) the relative prevalence of the most common comorbid conditions to each other in irritable bowel will be the same as their relative prevalence in the general population; (2) the number of comorbid conditions will be correlated with psychological measures; and (3) patients with few comorbid conditions will be more likely to have a biological basis for bowel symptoms than will patients with many comorbid conditions. Study I will compare health care visits of 3,153 irritable bowel patients to gender and age matched healthy controls, and to 6,153 patients with gastroesophageal reflux and 517 with inflammatory bowel disease over 4 years. Study II will compare number of comorbid non-gastrointestinal conditions and symptoms to psychometric measures of anxiety, depression, somatization, and childhood modelling of illness behavior in 700 irritable bowel patients plus 1,100 with abdominal pain, constipation, or diarrhea. Study III will prospectively test a comprehensive panel of physiological and psychological factors believed to contribute to the symptoms of irritable bowel in 200 patients. A hierarchical cluster analysis of the first 100 patients will be used to determine whether (1) irritable bowel patients meeting Rome II criteria are a heterogeneous group consisting of subgroups associated with different etiological mechanisms and (2) whether number of comorbid conditions distinguishes groups with predominantly psychological etiologies from groups with predominantly biological etiologies. A cluster analysis of the second 100 patients will be used to confirm the reproducibility of the groups identified in the first clustere analysis and which variables distinguish among the groups. These studies will be done in collaboration with the University of Washington, Group Health Cooperative of Puget Sound, and the Mayo Clinic in Scottsdale, AZ.